Activity and pharmacodynamics of 21-day topotecan infusion in patients with ovarian cancer previously treated with platinum-based chemotherapy

Howard Hochster, Scott Wadler, Carolyn Runowicz, Leonard Liebes, Henry Cohen, Robert Wallach, Joan Sorich, Beth Taubes, James Speyer

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


Purpose: Twenty-one-day topotecan infusion was administered as second- line therapy in patients with previously treated ovarian cancer (based on our prior favorable phase I experience) to determine its activity, time to progression, and pharmacodynamics. Patients and Methods: Ovarian cancer patients with measurable lesions and one prior platinum-containing regimen were eligible. Topotecan 0.4 mg/m2/d 21-day continuous ambulatory intravenous infusion, with appropriate dose modifications for toxicity, was administered every 28 days. Weekly blood levels of topotecan and topoisomerase. 1 (topo-1) levels in peripheral-blood mononuclear cells (PBMCs) were determined for pharmacodynamic correlation. Results: Twenty-four patients were entered onto the study (six cisplatin-refractory, five relapsing within < 6 months and 13 relapsing > 6 months after platinum-based therapy). A total of 128 cycles of topotecan (median, four cycles per patient; range, one to 12 cycles) were administered. The major toxicity was neutropenia (29% grade 3 in all cycles and 4% grade 4). One episode of grade 4 thrombocytopenia (4%) occurred. Fifty-two percent of the patients had anemia that required transfusions. Eight of 23 patients with measurable disease (35%; 95% confidence interval [CI], 15% to 54%) had partial responses (PRs) lasting longer than I month. Two of these patients had minor residual computed tomographic changes but had clinical complete remissions that lasted up to 53 weeks while they were not undergoing further therapy. One patient with nonmeasurable disease had a PR (by CA-125-criteria) that lasted 6 months, for an overall response rate of 38% in nine of 24 patients (95% CI, 18% to 57%). The median time to progression was 26 weeks. Pharmacodynamic analysis demonstrated a statistically significant decrease in free PBMC topo- 1 level at weeks 2 and 3 of drug administration. There was a strong statistical correlation between the decrease in free topo-1 levels and increasing area under the curve (AUC) far topotecan. This was confirmed in a pharmacodynamic model. Conclusion: Twenty-one-day infusion is a well- tolerated method of administering topotecan. Pharmacodynamic studies demonstrate correlations between (1) the week of infusion and the PBMC topo-1 level, (2) the AUC of topotecan and the decrease in topo-1 levels, and (3) the change in topo- 1 level and the neutrophil nadir. The objective response rate of 35% to 38% (95% CI, 15% to 57%) in this small multicenter study is at the upper level far topotecan therapy in previously treated ovarian cancer. Prolonged topotecan administration therefore warrants further investigation in larger, randomized studies comparing this 21-day schedule with the once- daily-for-5-days schedule.

Original languageEnglish (US)
Pages (from-to)2553-2561
Number of pages9
JournalJournal of Clinical Oncology
Issue number8
StatePublished - Aug 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


Dive into the research topics of 'Activity and pharmacodynamics of 21-day topotecan infusion in patients with ovarian cancer previously treated with platinum-based chemotherapy'. Together they form a unique fingerprint.

Cite this